New Issues in Newborn Screening for Phenylketonuria and
Congenital Hypothyroidism: A Commentary from the Committee on
Genetics of the American Academy of Pediatrics

The following policy statement was developed by the American
Academy
of Pediatrics Committee on Genetics and published in Pediatrics
1982;69:104-6. CDC believes that it is an excellent statement of
public health policy regarding newborn screening of phenylketonuria
and congenital hypothyroidism and concurs with its recommendations.

Screening for phenylketonuria (PKU) and congenital
hypothyroidism
(CH) is of concern to parents, physicians, and public health
professionals. Parents have an abiding interest in a predictive
activity that can prevent disease in their offspring. Physicians
and
their consultants must counsel parents and interpret a positive
screening test. Public health personnel are concerned with the
specificity and sensitivity, efficiency, and effectiveness of
newborn
screening.

The Committee on Genetics has previously published
recommendations
on newborn screening for PKU and CH (1). Further recommendations
are
required because PKU and CH screening are widely practiced joint
procedures in the newborn and because most full-term newborn
infants
are now being discharged from North American nurseries within the
first 3 days after birth. This new practice is likely to have an
effect on the validity of newborn screening and on screening for
PKU,
in particular.

A recent statement from the Committee on Fetus and Newborn
(Pediatrics 65:651, 1980) addressed the problem of so-called "in
and
out deliveries." However, the statement was ambiguous on the issue
of
whether such infants should be screened routinely on the initial
discharge from the nursery. The Committee on Genetics believes
that
all infants, regardless of age, should be screened for PKU and CH
at
discharge from the nursery.

The Committee believes that screening is not the equivalent of
diagnosis; some cases of PKU and CH will inevitably be missed by
screening. Whereas an important reason for missed cases may be the
biology of the target disorders, none should slip through the
screening mesh because of flaws in the program and its components.
Accordingly, we have examined the allied problems of initial
screening
and rescreening at a later age, in relation to early discharge from
the nursery and our previous recommendations (1). The new
statement
emphasizes 4 issues; 1) organization of newborn screening programs
for
PKU and CH; 2) biologic adequacy of the blood sample and how it may
influence the rate of false-negative results, and the need for
routine
rescreening; 3) performance of the screening method and how it may
influence the frequency of false-negative test results; and 4)
disorders of tetrahydrobiopterin homeostasis and their significance
for diagnosis and treatment of infants with positive PKU tests.
RECOMMENDATIONS

An adequate screening PROGRAM for the persistent

hyperphenylaninemias (PHP), including PKU, and for CH (in its
various
forms) should assure: a) total participation by the eligible
population; b) notification of parents about newborn screening and
their participation in this activity; c) reliable and prompt
performance of the screening test; d) prompt follow-up of subjects
with positive tests; e) accurate diagnosis of subjects with
confirmed
positive tests; f) appropriate counseling and treatment of
patients.

2. A blood SAMPLE should be obtained from every infant before
he/she leaves the nursery, regardless of age.* Siblings of
children
with PKU/PHP and CH deserve special priority for collection of the
sample. An adequate sample is defined as follows: a) for PKU/PHP,
it
is heel blood obtained as close as possible to time of discharge
from
the nursery in a full-term infant (cord blood is not sufficient);
b)
for CH, it is cord blood at birth or heel blood at discharge; c) in
a
premature infant, for any infant receiving parenteral feeding, or
any
newborn infant being treated for illness, it is a blood sample
obtained at or near the seventh day of age.

3. Infants initially screened before 24 hours of age should be
rescreened for PKU/PHP because the probability of missing cases by
the
initial screening test is greatly increased. The repeat screening
test should be completed before the third week of life.

4. Accurate ANALYSIS requires meticulous standardization of
the
screening method. Accuracy is improved when the cutoff level
delineating an abnormal result is defined and specificity of the
test
is monitored regularly; to do so requires a high volume of samples
per
unit time. This analytical component in the program should be
centralized to enhance ongoing evaluation of efficiency, accuracy,
participation, and adequacy of samples.

5. All patients with persistent hyperphenylalaninemia should
be
investigated to rule out the tetrahydrobiopterin-deficient forms of
PKU.

6. Systematic follow-up of infants with positive CH screening
tests is necessary to evaluate the efficacy of CH prevention.
COMMENTARY

Phenylketonuria and Other Forms of Persistent
Hyperphenylalaninemia Associated with Disease.

Early diagnosis and treatment largely prevent the mental
retardation associated with untreated PKU, and a properly executed
program is clearly cost effective (2). PREVENTION requires an
adequate PROGRAM, a satisfactory SAMPLE for the screening test, and
reliable ANALYSIS of the sample.

1.1. The Program. Programs that reach every infant, perform
the
test reliably, provide timely follow-up of subjects with positive
tests, assure accurate diagnosis, and provide appropriate
counseling
and treatment conform to published guidelines (1,3). Programs
lacking
any of these components cannot be recommended. Missed cases of
PKU/PHP in screening programs may reflect faults of program
organization, in particular, failure to obtain the blood sample or
to
perform a reliable analysis. On the other hand, cases can be
missed
because of biologic variation in the expression of
hyperphenylalaninemia and are not necessarily the result of
negligence
in screening.

1.2. The Sample. Cases of PKU have been missed because the
level
of blood phenylalanine was not elevated above normal, even after
the
third day of life (B. Wilcken et al., personal communications,
1981).
In general, however, the chance of false-negative test results for
PKU
and other forms of PHP is greater when the blood sample is obtained
before 72 hours of age. This statement is based on the following
evidence (4-8). 1) Serial measurements in PKU infants during the
first 3 days of life show that blood phenylalanine concentrations 4
mg/100 ml are more likely to occur in this period than after 72
hours
of age; 2) The incidence of false-negative test results in PKU
(either
actual or predicted on statistical grounds) is higher in the first
3
days of life than in older infants.

Extrapolations from available data suggest that 16.1% of PKU
cases
could be missed on the first day (1 to 24 hours) of life because
the
screened blood sample contained 4 mg of phenylalanine/100 ml; 2.2%
of
cases could be missed when screening is done on the second day (25
to
48 hours); and 0.3% on the third day (49 to 72 hours) of life.
However, these are only statistical estimates of the frequency of
missed cases. They are based on the distribution of blood
phenylalanine in the PKU and non-PKU populations during the first 3
days of life where skewness and other factors in the variance
contribute to the probability statements. An evaluation of routine
repeat blood screening (9) indicated that routine follow-up blood
testing of infants for PKU was not productive.

It is now firmly established (7,8,10) that cord blood cannot be
used for PKU/PHP screening. Whether or not feeding practices
influence the accuracy of screening in the first 3 days of life
remains uncertain; it is the opinion of the Committee that this
factor
is of only minor importance, and the Recommendations should be
followed regardless of the feeding protocol.

1.3. The Analytical Method. Accurate analysis of the sample
is a
critical facet of prevention. The Guthrie test is a threshold
(cutoff) method that estimates phenylalanine concentration above a
certain level in the blood sample. Quantitative methods permit the
age-specific distribution of phenylalanine to be described and the
corresponding cutoff level to be defined statistically. In
practice,
either method has predictive validity for PKU screening.

1.4. Tetrahydrobiopterin-deficient PKU. Infants with
disorders
of tetrahydrobiopterin homeostasis are likely to experience
progressive neurologic deterioration when treated with
low-phenylalanine diet alone (2,11,12). Current estimates indicate
that 0.5% to 3% of infants with persistent hyperphenylalaninemia
have
a disorder of tetrahydrobiopterin metabolism. Their prognosis is
quite different from that for infants with benign PHP or typical
PKU
treated and counseled in the conventional manner. Accordingly,
prognosis for any patient with persistent hyperphenylalaninemia
must
be guarded, until experience with early diagnosis and treatment of
tetrahydrobiopterin-deficient hyperphenylalaninemia has been
accumulated and evaluated. Prompt consultation with the
appropriate
regional center for further investigation is recommended for all
cases

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